OBJECTIVETo investigate the effect of micronized fenofibrate on vascular endothelial function in patients with hypertriglyceridemia.

METHODSUsing high-resolution ultrasound, we measured flow- and nitroglycerin-induced dilatation of the brachial artery in 30 patients with hypertriglyceridemia before and after treatment with micronized fenofibrate at a dose of 200 mg once daily for 4 weeks. Simultaneously, both serum lipid and plasma endothelin (ET) levels were determined.

RESULTSAfter micronized fenofibrate therapy, serum triglyceride (TG) levels decreased significantly (P < 0.05). Plasma ET levels also decreased markedly [(82.66 +/- 15.46) microg/L vs. (106.22 +/- 19.16) microg/L, P < 0.001]. Flow-induced vasodilatation was much improved (11.0% +/- 9.0% vs 2.7% +/- 2.0%, P < 0.01). However, no significant changes in vasodilatation occurred in response to nitroglycerin (16.2% +/- 6.0% vs 15.0% +/- 5.0%, P > 0.05) in patients with hypertriglyceridemia.

CONCLUSIONSMicronized fenofibrate can improve impaired endothelium-dependent vasodilatation in patients with hypertriglyceridemia. Improving endothelial function may also be the mechanism responsible for the beneficial effects of micronized fenofibrate.

Adult ; Endothelium, Vascular ; drug effects ; physiology ; Female ; Fenofibrate ; pharmacology ; therapeutic use ; Humans ; Hypertriglyceridemia ; drug therapy ; Male ; Middle Aged ; Vasodilation ; drug effects

BACKGROUNDAgeing is associated with increased incidence of dyslipidemia. To investigate potential molecular mechanisms, the effects of age and fibrate administration on peroxisome proliferator-activated receptor alpha (PPARalpha) expression in livers of young and old rats were studied.

METHODSA total of 16 young (2-month-old) and 16 old rats (24-month-old) were randomly assigned to a control group and fenofibrate group (fenofibrate in a total therapeutic dosage of 0.5% in ratio to each treated rat weight in 14 days). RT-PCR was applied to evaluate hepatic mRNA expression of PPARalpha and its target genes. Western blotting was used to determine PPARalpha protein level in liver tissue.

RESULTSWhen compared with 2-month-old rats, the liver tissue from 24-month-old rats showed reduced expression of PPARalpha mRNA (52%, P < 0.05) and protein (109%, P < 0.01). Consequently, the mRNA levels of PPAR target genes, LPL, ACO, ACS and CPT-1 were markedly lowered by 19%, 8%, 13% and 9% respectively, and apoCIII increased by 24% in livers from 24-month-old rats, compared with values obtained from 2-month-old rats (P < 0.05). Fenofibrate therapy significantly lowered plasma triglyceride and total cholesterol levels in old rats, accompanied with improvement in hepatic expression of genes, including LPL, ACO, ACS, CPT-1 and apoCIII, but no change was found in PPARalpha expression in livers from either 24-month or 2-month-old rats.

CONCLUSIONSThe decrease in the hepatic PPARalpha expression is probably directly related to the lipid metabolic disturbances observed in old animals. The beneficial effects of fenofibrate administration in old rats suggests that fibrates may be useful for treating lipid disturbances in old people.

Aging ; metabolism ; Animals ; Fenofibrate ; pharmacology ; therapeutic use ; Hyperlipidemias ; drug therapy ; etiology ; Lipids ; blood ; Liver ; metabolism ; Male ; PPAR alpha ; genetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the effects of peroxisome proliferator-activated receptor (PPAR) alpha agonist Fenofibrate (FF) on energy metabolism and histology in isoproterenol (Iso) induced acute myocardial ischemic injury model.

METHODSMale Wistar rats were randomly divided into control group, Iso group (5 mg/kg, i.p.) and FF group (80 mgxkg(-1)xd(-1) per gavage for 7 days, then Iso 5 mg/kg, i.p. n = 30 each). Twenty-four hours post Iso, heart weight/body weight ratio, myocardial histopathological changes (HE staining), serum and myocardial free fatty acids (FFA) levels, the myocardial protein expression of PPARalpha (Western blot) were determined.

RESULTCompared with the control group, pathological myocardial injuries were observed under light microscope in Iso treated hearts and FF pretreatment could significantly attenuate these changes [necrotic area: 0 vs (10.00 +/- 3.00)% vs (7.36 +/- 2.60)%], the heart weight/body weight ratio, FFA in serum (501.17 +/- 43.69 vs 939.53 +/- 69.51 vs 736.53 +/- 70.30 micromol/L) and myocardium (62.01 +/- 9.19 vs 140.59 +/- 19.34 vs 116.28 +/- 14.03 micromol/L) were significantly increased while myocardial protein expressions of PPARalpha (251.57 +/- 10.95 vs 191.97 +/- 10.74 vs 215.08 +/- 9.61) was significantly downregulated in the Iso group and FF pretreatment could significantly attenuate these changes (all P < 0.05).

CONCLUSIONOur data suggested that the FFA utilization was decreased in Iso induced acute myocardial ischemic injury and FF could attenuate Iso induced myocardial damage via activating PPARalpha signaling pathway.

Animals ; Disease Models, Animal ; Energy Metabolism ; Fenofibrate ; pharmacology ; therapeutic use ; Isoproterenol ; Male ; Myocardial Ischemia ; chemically induced ; metabolism ; prevention & control ; Myocardial Reperfusion Injury ; chemically induced ; metabolism ; prevention & control ; Myocardium ; metabolism ; PPAR alpha ; metabolism ; Rats ; Rats, Wistar

Metformin has been reported to increase the expression of the glucagon-like peptide-1 (GLP-1) receptor in pancreatic beta cells in a peroxisome proliferator-activated receptor (PPAR)-alpha-dependent manner. We investigated whether a PPARalpha agonist, fenofibrate, exhibits an additive or synergistic effect on glucose metabolism, independent of its lipid-lowering effect, when added to metformin. Non-obese diabetic Goto-Kakizaki (GK) rats were divided into four groups and treated for 28 days with metformin, fenofibrate, metformin plus fenofibrate or vehicle. The random blood glucose levels, body weights, food intake and serum lipid profiles were not significantly different among the groups. After 4 weeks, metformin, but not fenofibrate, markedly reduced the blood glucose levels during oral glucose tolerance tests, and this effect was attenuated by adding fenofibrate. Metformin increased the expression of the GLP-1 receptor in pancreatic islets, whereas fenofibrate did not. During the intraperitoneal glucose tolerance tests with the injection of a GLP-1 analog, metformin and/or fenofibrate did not alter the insulin secretory responses. In conclusion, fenofibrate did not confer any beneficial effect on glucose homeostasis but reduced metformin's glucose-lowering activity in GK rats, thus discouraging the addition of fenofibrate to metformin to improve glycemic control.
Animals ; Blood Glucose/metabolism ; Body Weight/drug effects ; Diabetes Mellitus, Experimental/*drug therapy/*metabolism ; Drug Therapy, Combination ; Feeding Behavior/drug effects ; Fenofibrate/*pharmacology/therapeutic use ; Glucagon-Like Peptide 1/agonists/metabolism ; Glucose/*metabolism ; Glucose Tolerance Test ; Homeostasis/*drug effects ; Immunohistochemistry ; Injections, Intraperitoneal ; Insulin-Secreting Cells/drug effects/metabolism/pathology ; Lipid Metabolism/drug effects ; Male ; Metformin/*pharmacology/therapeutic use ; Peptides/administration & dosage/pharmacology ; Rats ; Receptors, Glucagon/metabolism ; Venoms/administration & dosage/pharmacology

The aim of this study was to investigate the possible beneficial effects of Fenofibrate on renal ischemia-reperfusion injury (IRI) in mice and its potential mechanism. IRI was induced by bilateral renal ischemia for 60 min followed by reperfusion for 24 h. Eighteen male C57BL/6 mice were randomly divided into three groups: sham-operated group (sham), IRI+saline group (IRI group), IRI+Fenofibrate (FEN) group. Normal saline or Fenofibrate (3 mg/kg) was intravenously injected 60 min before renal ischemia in IRI group and FEN group, respectively. Blood samples and renal tissues were collected at the end of reperfusion. The renal function, histopathologic changes, and the expression levels of pro-inflammatory cytokines [interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α) and IL-6] in serum and renal tissue homogenate were assessed. Moreover, the effects of Fenofibrate on activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling and peroxisome proliferator-activated receptor-α (PPAR-α) were also measured in renal IRI. The results showed that plasma levels of blood urea nitrogen and creatinine, histopathologic scores and the expression levels of TNF-α, IL-8 and IL-6 were significantly lower in FEN group than in IRI group. Moreover, Fenofibrate pretreatment could further induce PI3K/Akt signal pathway and PPAR-α activation following renal IRI. These findings indicated PPAR-α activation by Fenofibrate exerts protective effects on renal IRI in mice by suppressing inflammation via PI3K/Akt activation. Thus, Fenofibrate could be a novel therapeutic alternative in renal IRI.
Animals ; Base Sequence ; DNA Primers ; Enzyme Activation ; Fenofibrate ; pharmacology ; therapeutic use ; Inflammation ; drug therapy ; Kidney ; blood supply ; Male ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Real-Time Polymerase Chain Reaction ; Reperfusion Injury ; drug therapy ; Signal Transduction